Trazodone and mirtazapine: A possible opioid involvement in their use (at low dose) for sleep?

The efficacy of each antidepressant available has been found equal to that of amitriptyline in double-blind studies. However, a few of them are being prescribed (at under-therapeutic doses) for sleep, in non-depressed persons, when there are relative contraindications for sedative-hypnotics. Following previous studies regarding the antinociceptive mechanisms of various antidepressants, we suggest that the involvement of the opioid system in some of the antidepressants' mechanism of action may contribute to these medications' use for the induction and maintenance of sleep. The mostly prescribed antidepressants for sleep are trazodone (a weak, but specific inhibitor of the synaptosomal uptake of serotonin, that also binds to alpha-1 and alpha-2 adrenoreceptor sites) and mirtazapine (a postsynaptic drug which enhances noradrenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central alpha-2-auto- and hetero-adrenoreceptors). In our previous studies when ICR mice were tested with a hotplate analgesia meter, both trazodone and mirtazapine induced, a naloxone-reversible antinociceptive effect following i.p administration. Summing up the various interactions of trazodone and mirtazapine with opioid, noradrenergic and serotonergic agonists and antagonists, we found that the antinociceptive effect of trazodone is influenced by the opioid receptor subtypes mu and delta (and a clear 5-HT mechanism of antinociception), while the antinociceptive effect of mirtazapine is mainly influenced by kappa and mu opioid receptor subtype (combined with both serotonergic and noradrenergic receptors). This opioid profile of the two drugs may be one of the explanations to their efficacy in the treatment of insomnia, when sedatives (either benzodiazepines or the non-benzodiazepine "Z-compounds") cannot be prescribed.

Dietary Energy Restriction Ameliorates Cognitive Impairment in a Mouse Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) is one of the most common causes of neurological damage in young people. It was previously reported that dietary restriction, by either intermittent fasting (IF) or daily caloric restriction (CR), could protect neurons against dysfunction and degeneration in animal models of stroke and Parkinson's disease. Recently, several studies have shown that the protein Sirtuin 1 (SIRT1) plays a significant role in the induced neuroprotection following dietary restriction. In the present study, we found a significant reduction of SIRT1 levels in the cortex and hippocampus in a mouse model of mild weight-drop closed head TBI. This reduction was prevented in mice maintained on IF (alternate day fasting) and CR initiated after the head trauma. Hippocampus-dependent learning and memory (measured using a novel object recognition test) was impaired 30 days post-injury in mice fed ad libitum, but not in mice in the IF and CR groups. These results suggest a clinical potential for IF and/or CR as an intervention to reduce brain damage and improve functional outcome in TBI patients.

Cannabis use during pregnancy: Are we at the verge of defining a "fetal cannabis spectrum disorder"?

Cannabis is probably the drug most commonly used globally since ancient times. Following the trend of legalization of access to cannabis in several Western countries, its use has increased in North America over the past few years. In spite of warnings of the potential hazards associated with in-utero exposure to cannabis, approximately 10% of pregnant women in an American study reported using cannabis in recent years, and most of them on a daily basis. Significant effects of prenatal cannabis exposure have been found on children's sleep, cognitive functions (memory and scholastic skills), as well as on executive (frontal lobe) functions (reasoning, attention, impulsivity, and motivation), and affective (depression) and anxiety symptoms throughout the stages of development. Following the presentation of two case vignettes, we integrate the published information on outcomes of maternal use of cannabis during pregnancy on the developing fetus and the "soft" neurological deficits and neuro-behavioral disturbances manifested by them from early childhood and evolving to peaks in adolescence. Taken together, these data serve to define what we call a heretofore unspecified "fetal cannabis spectrum disorder".

Annexin A2, autoimmunity, anxiety and depression.

OBJECTIVES: Antiphospholipid syndrome (APS) is associated with neurological manifestations and one of the novel autoantigens associated with this disease is Annexin A2 (ANXA2). In this work we have examined the effect of high levels of autoantibodies to ANXA2 on the brain in a mouse model. METHODS: Recombinant ANXA2 emulsified in adjuvant was used to immunize mice while mice immunized with adjuvant only served as controls. At peak antibody levels the animal underwent behavioral and cognitive tests and their brains were examined for ANXA2 immunoglobulin G (IgG) and expression of ANXA2 and the closely linked protein p11. RESULTS: Very high levels of anti-ANXA2 antibodies (Abs) were associated with reduced anxiety in the open field 13.14% ± 0.89% of the time in the center compared to 8.64% ± 0.91% observed in the control mice (p < 0.001 by t-test). A forced swim test found significantly less depression manifested by immobility in the ANXA2 group. The changes in behavior were accompanied by a significant reduction in serum corticosteroid levels of ANXA2 group compared to controls. Moreover, higher levels of total IgG and p11 expression were found in ANXA2 group brains. Lower levels of circulating anti-ANXA2 Abs were not associated with behavioral changes. CONCLUSIONS: We have established an animal model with high levels of anti-ANXA2 Abs which induced IgG accumulation in the brain and specific anxiolytic and anti-depressive effects. This model promises to further our understanding of autoimmune disease such as APS and to provide better understanding of the role of the ANXA2-p11 complex in the brain.

Post-trauma administration of the pifithrin-α oxygen analog improves histological and functional outcomes after experimental traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Programmed death of neuronal cells plays a crucial role in acute and chronic neurodegeneration following TBI. The tumor suppressor protein p53, a transcription factor, has been recognized as an important regulator of apoptotic neuronal death. The p53 inactivator pifithrin-α (PFT-α) has been shown to be neuroprotective against stroke. A previous cellular study indicated that PFT-α oxygen analog (PFT-α (O)) is more stable and active than PFT-α. We aimed to investigate whether inhibition of p53 using PFT-α or PFT-α (O) would be a potential neuroprotective strategy for TBI. To evaluate whether these drugs protect against excitotoxicity in vitro, primary rat cortical cultures were challenged with glutamate (50mM) in the presence or absence of various concentrations of the p53 inhibitors PFT-α or PFT-α (O). Cell viability was estimated by LDH assay. In vivo, adult Sprague Dawley rats were subjected to controlled cortical impact (CCI, with 4m/s velocity, 2mm deformation). Five hours after injury, PFT-α or PFT-α (O) (2mg/kg, i.v.) was administered to animals. Sensory and motor functions were evaluated by behavioral tests at 24h after TBI. The p53-positive neurons were identified by double staining with cell-specific markers. Levels of mRNA encoding for p53-regulated genes (BAX, PUMA, Bcl-2 and p21) were measured by reverse transcription followed by real time-PCR from TBI animals without or with PFT-α/PFT-α (O) treatment. We found that PFT-α(O) (10 µM) enhanced neuronal survival against glutamate-induced cytotoxicity in vitro more effectively than PFT-α (10 µM). In vivo PFT-α (O) treatment enhanced functional recovery and decreased contusion volume at 24h post-injury. Neuroprotection by PFT-α (O) treatment also reduced p53-positive neurons in the cortical contusion region. In addition, p53-regulated PUMA mRNA levels at 8h were significantly reduced by PFT-α (O) administration after TBI. PFT-α (O) treatment also decreased phospho-p53 positive neurons in the cortical contusion region. Our data suggest that PFT-α (O) provided a significant reduction of cortical cell death and protected neurons from glutamate-induced excitotoxicity in vitro, as well as improved neurological functional outcome and reduced brain injury in vivo via anti-apoptotic mechanisms. The inhibition of p53-induced apoptosis by PFT-α (O) provides a useful tool to evaluate reversible apoptotic mechanisms and may develop into a novel therapeutic strategy for TBI.

Mild closed head injury promotes a selective trigeminal hypernociception: implications for the acute emergence of post-traumatic headache.

BACKGROUND: Headache is one of the most common symptoms following traumatic head injury. The mechanisms underlying the emergence of such post-traumatic headache (PTH) remain unknown but may be related to injury of deep cranial tissues or damage to central pain processing pathways, as a result of brain injury. METHODS: A mild closed head injury in mice combined with the administration of cranial or hindpaw formalin tests was used to examine post-traumatic changes in the nociceptive processing from deep cranial tissues or the hindpaw. Histological analysis was used to examine post-traumatic pro-inflammatory changes in the calvarial periosteum, a deep cranial tissue. RESULTS: At 48 h after head injury, mice demonstrated enhanced nociceptive responses following injection of formalin into the calvarial periosteum, a deep cranial tissue, but no facilitation of the nociceptive responses following injection of formalin into an extracranial tissue, the hindpaw. Mice also showed an increase in the number of activated periosteal mast cells 48 h following mild head trauma, suggesting an inflammatory response. CONCLUSION: Our study demonstrates that mild closed head injury is associated with enhanced processing of nociceptive information emanating from trigeminal-innervated deep cranial tissues, but not from non-cranial tissues. Based on these finding as well as the demonstration of head injury-evoked degranulation of calvarial periosteal mast cells, we propose that inflammatory-evoked enhancement of peripheral cranial nociception, rather than changes in supraspinal pain mechanisms play a role in the initial emergence of PTH. Peripheral targeting of nociceptors that innervate the calvaria may be used to ameliorate PTH pain.

A study on the mechanism by which MDMA protects against dopaminergic dysfunction after minimal traumatic brain injury (mTBI) in mice.

Driving under methylenedioxymethamphetamine (MDMA) influence increases the risk of being involved in a car accident, which in turn can lead to traumatic brain injury. The behavioral deficits after traumatic brain injury (TBI) are closely connected to dopamine pathway dysregulation. We have previously demonstrated in mice that low MDMA doses prior to mTBI can lead to better performances in cognitive tests. The purpose of this study was to assess in mice the changes in the dopamine system that occurs after both MDMA and minimal traumatic brain injury (mTBI). Experimental mTBI was induced using a concussive head trauma device. One hour before injury, animals were subjected to MDMA. Administration of MDMA before injury normalized the alterations in tyrosine hydroxylase (TH) levels that were observed in mTBI mice. This normalization was also able to lower the elevated dopamine receptor type 2 (D2) levels observed after mTBI. Brain-derived neurotrophic factor (BDNF) levels did not change following injury alone, but in mice subjected to MDMA and mTBI, significant elevations were observed. In the behavioral tests, haloperidol reversed the neuroprotection seen when MDMA was administered prior to injury. Altered catecholamine synthesis and high D2 receptor levels contribute to cognitive dysfunction, and strategies to normalize TH signaling and D2 levels may provide relief for the deficits observed after injury. Pretreatment with MDMA kept TH and D2 receptor at normal levels, allowing regular dopamine system activity. While the beneficial effect we observe was due to a dangerous recreational drug, understanding the alterations in dopamine and the mechanism of dysfunction at a cellular level can lead to legal therapies and potential candidates for clinical use.

Enriched environment improves the cognitive effects from traumatic brain injury in mice.

To date, there is yet no established effective treatment (medication or cognitive intervention) for post-traumatic brain injury (TBI) patients with chronic sequelae. Enriched environment (EE) has been recognized of importance in brain regulation, behaviour and physiology. Rodents reared in, or pre-exposed to EE, recovered better from brain insults. Using the concussive head trauma model of minimal TBI in mice, we evaluated the effect of transition to EE following a weight-drop (30g or 50g) induced mTBI on behavioural and cognitive parameters in mice in the Novel Object Recognition task, the Y- and the Elevated Plus mazes. In all assays, both mTBI groups (30g, 50g) housed in normal conditions were equally and significantly impaired 6 weeks post injury in comparison with the no-mTBI (p<0.001 and p<0.03, respectively) and the mTBI+EE groups (p<0.001 for the 30g, and p<0.017 for the 50g). No differences were found between the control and the EE mice. Two separate finding emerge: (1) the significantly positive effects of the placement in EE following mTBI, on the rehabilitative process of the tested behaviours in the affected mice; (2) the lack of difference between the groups of mice affected by 30g or by 50g. Further studies are needed in order to characterize the exact pathways involved in the positive effects of the EE on mice recovery from mTBI. Possible clinical implications indicate the importance of adapting correlates of EE to humans, i.e., prolonged and intensive physical activity - possibly combined with juggling training and intensive cognitive stimulation.

Hyperbaric oxygen-induced seizures cause a transient decrement in cognitive function.

Hyperbaric oxygen-induced seizures are classified as brief, generalized tonic-clonic seizures. They are believed to cause no residual cognitive damage, although this has not been investigated in depth. In the present study, we examined whether hyperbaric oxygen-induced seizures cause impairment of behavioral and cognitive abilities. Cognitive status was assessed using four behavioral tests: Y-maze, novel object recognition, the elevated plus maze, and a passive avoidance task. Three time intervals were examined: 24h, and 7 and 30 days after the seizures. We found transient impairment of performance in the compressed group on three tests (the novel object recognition paradigm, the Y-maze paradigm, and the passive avoidance task). On the elevated plus maze test, the impairment persisted. The time interval to the appearance of deficits and to eventual recovery was not the same for the different tests. We conclude that hyperbaric oxygen-induced seizures result in transient impairment of performance on behavioral tests in a mouse model. Further investigation is required to establish the mechanism and location of injury, and to determine whether the performance decrement on the elevated plus maze test represents permanent damage or transient damage with slow resolution. These new findings should be taken into account when planning hyperbaric oxygen treatments, to ensure that the chosen protocol is therapeutic yet minimizes the risk of CNS oxygen toxicity.

The nuclear factor erythroid 2-like 2 activator, tert-butylhydroquinone, improves cognitive performance in mice after mild traumatic brain injury.

Traumatic Brain injury affects at least 1.7 million people in the United States alone each year. The majority of injuries are categorized as mild but these still produce lasting symptoms that plague the patient and the medical field. Currently treatments are aimed at reducing a patient's symptoms, but there is no effective method to combat the source of the problem, neuronal loss. We tested a mild, closed head traumatic brain injury model for the effects of modulation of the antioxidant transcription factor Nrf2 by the chemical activator, tert-butylhydroquinone (tBHQ). We found that post-injury visual memory was improved by a 7 day course of treatment and that the level of activated caspase-3 in the hippocampus was reduced. The injury-induced memory loss was also reversed by a single injection at 30 min after injury. Since the protective stress response molecule, HSP70, can be upregulated by Nrf2, we examined protein levels in the hippocampus, and found that HSP70 was elevated by the injury and then further increased by the treatment. To test the possible role of HSP70, model neurons in culture exposed to a mild injury and treated with the Nrf2 activator displayed improved survival that was blocked by the HSP70 inhibitor, VER155008. Following mild traumatic brain injury, there may be a partial protective response and patients could benefit from directed enhancement of regulatory pathways such as Nrf2 for neuroprotection.

Minimal traumatic brain injury induce apoptotic cell death in mice.

In the United States, 1.4 million people suffer from traumatic brain injury (TBI) each year because of traffic, sports, or war-related injuries. The majority of TBI victims suffer mild to minimal TBI (mTBI), but most are released undiagnosed. Detailed pathologies are poorly understood. We characterized the microscopic changes of neurons of closed-head mTBI mice after increased unilateral trauma using hematoxylin and eosin (H&E) stain, and correlated it with the expression of the apoptotic proteins c-jun, p53, and BCL-2. Minimal damage to the brain increases the number of pyknotic appearing neurons and activates the apoptotic proteins in both hemispheres. Although minimal, increased impact was positively correlated with the increased number of damaged neurons. These results may explain the wide variety of behavioral and cognitive deficits closed-head mTBI causes in mice. Our cumulative results point to the pathological origin of post-concussion syndrome and may aid in the development of future neuroprotective strategies for the disease.

DHEAS repeated treatment improves cognitive and behavioral deficits after mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is characterized by diffused symptoms, which when combined are called "post-concussion syndrome". Dehydroepiandrosterone sulfate (DHEAS) is a neuroactive neurosteroid. Previously, we have reported that closed head mTBI causes long lasting cognitive deficits and depressive-like behavior. In the present study we describe the effects of DHEAS on the behavior of mice that suffered closed head mTBI. Following the induction of mTBI, mice were treated once a week with DHEAS (s.c. 20 mg/kg) and their performance in the passive avoidance test and the forced swimming test (FST) were evaluated 7, 30, 60 and 90 days post-injury. The most important interactions were between injury and injection (passive avoidance; p<0.001 and FST; p=0.001), meaning that DHEAS has beneficial effects only when given to injured animals. Our results demonstrate that the long-term cognitive and behavioral effects induced by mTBI may be improved by a repeated weekly treatment with DHEAS.

Deficits in spatial orientation of children with intrauterine growth retardation.

The spatial orientation of intrauterine growth retarded (IUGR) children versus age-matched controls was examined using two spatial tests. The first test was the radial arm maze (RAM), a navigational test frequently used in animal models. The second test was a subtest from the Kaufman assessment battery for children (K-ABC). The IUGR group comprised 28 children aged 6 years. The control group comprised 29 appropriate-for-gestational age children. The performance of the IUGR children was significantly inferior to controls in both tests. In the RAM test, the ratio between the correct entrances to the total entrances was significantly lower in the IUGR group than in the control group (P<0.001). In the K-ABC, the IUGR group could not perform as well as control children (P<0.001). These results suggest that spatial orientation in IUGR children is inferior to their age-matched controls, possibly contributing to their potential learning difficulties. The present results also suggest that the RAM can be potentially used to test spatial orientation of children at-risk.

Mild traumatic brain injury induces persistent cognitive deficits and behavioral disturbances in mice.

Victims of mild traumatic brain injury (mTBI) do not show clear morphological brain defects, but frequently suffer from long-lasting cognitive deficits, emotional difficulties and behavioral disturbances. In the present study, we investigated the effects of experimental mTBI in mice on cognition, spatial and non-spatial tasks, and depressive-like behavior in mice. Experimental brain injury was induced using a concussive head trauma, which creates the TBI by a weight-drop device. Different groups of mice were tested at 7, 30, 60, and 90 days post-injury for cognitive function (the swim T-maze and the passive avoidance test) and for depression-like behavior (the forced swimming test). These tests have been used infrequently in the past in mTBI research. Significant differences were observed between the injured mice compared to the controls in both the swim T-maze (day 30: p < 0.001) and passive avoidance (day 30: p < 0.05) tests. In addition, a significant difference was detected in the forced swimming test between the injured mice and the controls (day 7: p < 0.05; day 90: p < 0.01), which showed a depressive- like state in the injured animals beginning 7 days post-injury. These results demonstrate that persistent deficits in these tests of cognitive learning abilities and emergence of depressive-like behavior in injured mice are similar to those reported in human post-concussion syndrome.

The effect of mianserin add-on, on the intensity of opioid withdrawal symptoms during detoxification program--a randomized, double blind, placebo controlled, prospective study.

BACKGROUND: Based on pre-clinical studies regarding the interaction of various antidepressant drugs with the opioid system, we designed a clinical study to be carried out in the 'in-patient detoxification unit' within a large community centre for treatment of drugs dependent people. We evaluated the effect of mianserin add-on, on the intensity of opioid withdrawal symptoms in opiate dependent subjects undergoing medication-supported physical detoxification and integrated psychosocial and psychotherapeutic intervention for the treatment of dependence. METHODS: Mianserin (or placebo) was added to the routine medication protocol, during the 3-week in-patient phase of detoxification in a prospective, randomized, double blind, placebo controlled study. Mianserin (or placebo) was continued after discharge and patients were followed up for 3 months in order to evaluate relapse rates. Opiate withdrawal symptoms were assessed during the first 10 days, while depression and anxiety were assessed throughout the 3 months of study. RESULTS: From day 2 onward, patients in the study group showed significantly lower withdrawal symptoms than the control group patients and reached this peak faster (study group 2.8 days, control group 3.2 days, p<0.001). However, drop out rates were higher in the study group throughout the study period and only 13% of the study group patients, compared to 30% of the control group patients reached the end point. CONCLUSION: Though adding mianserin to the medication treatment during detoxification of opiate-dependent persons attenuated significantly both the intensity and the duration of withdrawal symptoms, the overall drop out rate was negatively influenced in the study group compared to the control group and fewer patients completed the study. Further study is needed in order to establish the origin of the paradox of higher drop out rates in the presence of attenuated intensity and duration of opiate withdrawal symptoms in the study group, and the clinical implications that should be drown.

Age-dependent differential expression of BACE splice variants in brain regions of tg2576 mice.

Plaques found in the brains of patients suffering from Alzheimer's disease (AD) mainly consist of beta-amyloid (Abeta), which is produced by sequential cleaving of amyloid precursor protein (APP) by two proteolytic enzymes, beta- and gamma-secretases. Any change in the fine balance between these enzymes and their substrate may contribute to the etio-pathogenesis of AD. Indeed, the protein level and enzymatic activity of beta-secretase (BACE), but not its mRNA level, were found elevated in brain areas of AD patients who suffer a high load of Abeta plaque formation. Similarly, increased BACE activity but no mRNA change was observed in a transgenic mouse model of AD, tg2576, in which over expression of the Swedish mutated human APP leads to Abeta plaque formation and learning deficits. Based on the recent demonstration of four BACE splice variants with different enzymatic activity, the discrepancy between BACE activity and mRNA expression may be explained by the altered BACE alternative splicing. To test this hypothesis, we studied the expression of all BACE splice variants in different brain areas of tg2576 mice at age of 4 months and 1 year old. We found developmental and regional differences between wild-type and tg2576 mice. Our results indicate that over expression of APP in tg2576 mice leads to the altered alternative splicing of BACE and the increase of its enzymatically more active splice variant (I-501).

Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity.

The importance of environment in the regulation of brain, behaviour and physiology has long been recognized in biological, social and medical sciences. Animals maintained under enriched conditions have clearly been shown to have better learning abilities than those maintained under standard conditions. However, the effects of environmental enrichment (EE) on immunity and emotionality have been less documented and remain questionable. Therefore, we investigated the effect of EE on natural killer (NK) cell activity, psychological stress responses and behavioural parameters. Male C3H mice were housed either in enriched or standard conditions for 6 weeks. Behaviour was then examined by the grip-strength test, staircase and elevated plus maze, and corticosterone levels and NK cell activity were measured. Furthermore, animals exposed to the stress paradigm, achieved by electric shock with reminders, were tested for freezing time in each reminder. Corticosterone levels were also measured. The EE mice showed decreased anxiety-like behaviour and higher activity compared to standard mice, as revealed by a greater percentage of time spent in the open arms of the elevated plus maze, and a higher rate of climbing the staircase. A shorter freezing time in the stress paradigm and no corticosterone level reactivity were measured in EE mice. In addition, NK cell activity in spleens of EE mice was higher than that demonstrated in those of standard mice. Thus, EE has a beneficial effect on anxiety-like behaviour, stress response and NK cell activity. The effect on NK cell activity is promising, due to the role of NK cells in host resistance.

Neuronal-binding antibodies from patients with antiphospholipid syndrome induce cognitive deficits following intrathecal passive transfer.

Antiphospholipid antibodies (aPL) have been suggested to play a role in causing cognitive and behavioral impairments. In the present study we investigated the pathogenic potential of aPL by intracerebro-ventricular (ICV) administration of immunoglobulins (IgG) from patients with antiphospholipid syndrome (APS). IgG, purified from the sera of four APS patients, was tested for binding to normal mouse brain by immunohistological staining. These IgG (7.5 microg) were injected ICV unilaterally to male C3H mice. Mice injected with IgG purified from pooled sera derived from healthy subjects served as controls. The mice were examined neurologically for motor function and coordination, and cognitively in a Morris water maze. The cognitive tests were performed with the experimenter blinded to the treatment. The performance of the mice in four separate experiments was compared by analysis of variance with repeated measures. IgG from one APS patient was found to bind best to neuronal structures in the hippocampus and cerebral cortex. Mice (n = 43) injected with this IgG performed worse in the water maze compared to the controls (n = 45) with significant effects of the aPL IgG on the overall performance of the mice (treatment, P < 0.03), on learning throughout the experiment (treatment x day, P < 0.02) and on short term memory (treatment x day xtrial, P < 0.002). IgG injected from two of the three other patients also bound specifically to mouse brain neurons and produced an impairment in performance of the water maze. These results support the hypothesis that aPL that gain access to the central nervous system may play a direct role in the pathogenesis of neurological manifestations of APS.

Mianserin and trazodone significantly attenuate the intensity of opioid withdrawal symptoms in mice.

The aims of this study were to evaluate the effects of trazodone and mianserin on opioid-withdrawal symptoms in morphine-dependent mice. We used a comparative study of the effect of each drug on withdrawal symptoms in one model of acutely high-dose morphine-dependent mice, and two models (high-dose and lu-dose) of chronically morphine-dependent mice at the Tel Aviv University Sackler School of Medicine's laboratory.Trazodone, mianserin or both were given to the morphine-dependent mice together with a high dose of naloxone. Intensity of withdrawal symptoms was evaluated by tail-flick assay latencies and three behavioural measurements (rearing, jumping and grooming) in each group. Trazodone and mianserin, each separately,significantly attenuated withdrawal symptoms in all three models. However, the combined treatment of trazodone together with mianserin was not superior to each drug alone. The combination of trazodone and mianserin has no additive value to each drug alone in the control of withdrawal symptoms in opiate-dependent mice undergoing detoxification. When used in clinical settings, caution is needed in order to prevent the unknown influence of opioid-like drugs in medication-assisted detoxification programmes if complete opiate detoxification is the aim.

Closed-head minimal traumatic brain injury produces long-term cognitive deficits in mice.

Victims of minimal traumatic brain injury (mTBI) do not show clear morphological brain defects, but frequently suffer lasting cognitive deficits, emotional difficulties and behavioral disturbances. In the present study we adopted a non-invasive closed-head weight-drop mouse model to produce mTBI. We examined the effects of 20, 25, or 30 g weight drop 7, 30, 60 and 90 days following injury on mice's ability to perform the Morris water maze. The mice suffered profound long-lasting learning and memory deficits that were force- and time-dependent. Although the injured mice could acquire the task, they could not improve their initial escape latency by more than 50%, while normal mice improved by up to 450% (P<0.001). In order to directly compare the learning ability of individual mice following our mTBI we have devised a new measure which we term learning rate. We define learning rate as the rate the mouse improved its own performance in consecutive trials in a given experimental day. The learning rate of control mice increased linearly throughout the testing period with a slope of approximately 0.9. Injured mice that sustained 20 and 25 g weight drop could also improve their learning rate linearly but with a slope of only 0.2. Mice who sustained 30 g weight drop could not improve their learning rate linearly and reached a plateau after the third experimental learning day. These results indicate that the severity of injury may correlate with the degree of integration of the learning task. These cognitive deficits occurred without any other clear neurological damage, no evident brain edema, no notable damage to the blood-brain barrier and no early anatomical changes to the brain (observed by magnetic resonance imaging imaging). These results demonstrate that persistent deficits of cognitive learning abilities in mice, similar to those observed in human post-concussive syndrome, can follow mTBI without any anatomical damage to the brain and its surrounding tissue.